We are using electron microscopy to study the amount and physical properties of the polymer of deoxyhemoglobin S that forms in sickle erythrocytes upon deoxygenation. The electron microscopic studies are being correlated with results from nmuclear magnetic resonance spectroscopy and other methods to examine the physical, physiological and clinical variables that affect intracellular polymerization. These studies will allow us to test various hypotheses about the pathophysiology of sickle cell disease. We are also studying diphosphoglyceric acid analogs as possible inhibitors of deoxyhemoglobin S gelation and to clarify the transport of these compounds into the erythrocyte.